The epidemiology of campylobacter infections in Christchurch 1981-83.
The epidemiology of cases of campylobacter infection in Christchurch for 1981-83 is studied. The condition is the most common notifiable disease, occurring mainly in summer and in children under five years and young adults (15 to 35 years). There is evidence to suggest that a rural residence, associated with live animals, or handling raw meat, are risk factors. Clearance occurs within two months in 90% of cases.


Patient safety in primary and outpatient health care.
Primary care services provide an entry point into the health system which directly impact's people well-being and their use of other health care resources. Patient safety has been recognised as an issue of global importance for the past 10 years. Unsafe primary and ambulatory care results in greater morbidity, higher healthcare usage and economic costs. According to data from World Health Organization (WHO), the risk of a patient dying from preventable medical accident while receiving health care is 1 in 300, which is much higher than risk of dying while travelling in an airplane. Unsafe medication practices and inaccurate and delayed diagnosis are the most common causes of patient harm which affects millions of patients globally. However, majority of the work has been focussed on hospital care and there is very less understanding of what can be done to improve patient safety in primary care. Provision of safe primary care is priority as every day millions of people use primary care services across the world. The present paper focuses on various aspects of patient safety, especially in the primary care settings and also provides some potential solutions in order to reduce patient harm as much as possible. Some important challenges regarding patient safety in India are also highlighted.


Distinct processing of facial emotion of own-race versus other-race.
We investigated the neural basis underlying the effect of race on incidental facial emotional processing using functional MRI. Thirteen healthy Korean men underwent functional MRI while viewing photographs of Korean (own-race) and Caucasian (other-race) emotional faces while performing a sex discrimination task. Responses to other-race relative to own-race neutral faces replicated previous studies: activations were obtained in dorsolateral prefrontal cortex/medial frontal cortex. Direct contrasts between-race emotional faces (happy and sad) also showed differential effects: the contrast of own-race relative to other-race had more activations in limbic areas (amygdala and hippocampus), whereas the contrast of other-race relative to own-race had more activations in frontal, occipital, and parietal lobes. Our findings provide evidence for differential processing of emotional faces as a function of race.


L1CAM expression in endometrial carcinomas is regulated by usage of two different promoter regions.
The L1 cell adhesion molecule (L1CAM) was originally identified as a neural adhesion molecule involved in axon guidance. In many human epithelial carcinomas L1CAM is overexpressed and thereby augments cell motility, invasion and metastasis formation. L1CAM positive carcinomas are associated with bad prognosis. Recent data point out that L1CAM is regulated in a fashion similar to epithelial-mesenchymal transition (EMT). Previous studies have implied the transcription factors Slug and/or β-catenin in L1CAM transcriptional regulation. However, the regulation of human L1CAM expression at the transcriptional level is not well understood. To better understand the molecular basis of L1CAM transcriptional regulation, we carried out a detailed characterization of the human L1CAM promoter. We identified two transcription start sites, the first in front of a non-translated exon 0 (promoter 1) and the other next to the first protein-coding exon 1 (promoter 2). Both sites could be verified in endometrial carcinoma (EC) cell lines and appear to be used in a cell-type specific manner. The two identified promoter regions showed activity in luciferase reporter assays. Chromatin-IP analyses confirmed the in silico predicted E-boxes, binding sites for transcription factors Snail and Slug, as well as Lef-1 sites, which are related to β-catenin-mediated transcriptional regulation, in both promoters. Overexpression of β-catenin exclusively augmented activity of promoter 1 whereas Slug enhanced promoter 1 and 2 activity suggesting that both promoters can be active. Overexpression of β-catenin or Slug could upregulate L1CAM expression in a cell-type specific manner. Our results, for the first time, provide evidence that the L1CAM gene has two functionally active promoter sites that are used in a cell-type specific manner. Slug and β-catenin are involved L1CAM transcriptional regulation. Nevertheless, Slug rather than β-catenin levels are correlated with L1CAM expression in EC cell lines. Our findings suggest that the L1CAM transcriptional regulation is more complex than anticipated and this study provides the basis for a better understanding of L1CAM regulation in non-neuronal/tumor cells.


Improving Pathways to Care for Patients at High Psychosis Risk in Switzerland: PsyYoung Study Protocol.
Psychotic disorders are one of the main causes of chronic disability in young people. An at-risk mental state (ARMS) is represented by subclinical symptoms that precede the first episode of psychosis (FEP). The PsyYoung project aims to optimize the detection of an ARMS while reducing unnecessary psychiatric treatments. It investigates the effects of service changes on the referrals and outcomes of young people with ARMS or a FEP. Six psychiatric outpatient clinics in three cantons (Basel-Stadt, Vaud, and Geneva) participated in the project. They passed through an implementation phase including service changes and the adaptation of a standardized stepped care model for diagnosis and assessment, in addition to measures for increasing the awareness, networking and training of local professionals. All participating cantons had entered the implementation phase. By March 2023, there were 619 referrals to participating sites. A total of 163 patients (37% FEP and 31% ARMS) and 15 close relatives had participated in individual longitudinal assessments, and 26 patients participated in qualitative interviews. This national collaborative project addresses the issue of early intervention for emerging psychoses, and creates spaces for fruitful reflections and collaboration in Switzerland. The ultimate aim of PsyYoung is to harmonize clinical practices in early intervention of psychosis on a national level.


Applying Toyota production system techniques for medication delivery: improving hospital safety and efficiency.
The inpatient medication delivery system used at a large regional acute care hospital in the Midwest had become antiquated and inefficient. The existing 24-hr medication cart-fill exchange process with delivery to the patients' bedside did not always provide ordered medications to the nursing units when they were needed. In 2007 the principles of the Toyota Production System (TPS) were applied to the system. Project objectives were to improve medication safety and reduce the time needed for nurses to retrieve patient medications. A multidisciplinary team was formed that included representatives from nursing, pharmacy, informatics, quality, and various operational support departments. Team members were educated and trained in the tools and techniques of TPS, and then designed and implemented a new pull system benchmarking the TPS Ideal State model. The newly installed process, providing just-in-time medication availability, has measurably improved delivery processes as well as patient safety and satisfaction. Other positive outcomes have included improved nursing satisfaction, reduced nursing wait time for delivered medications, and improved efficiency in the pharmacy. After a successful pilot on two nursing units, the system is being extended to the rest of the hospital.


No large population of unbound or wide-orbit Jupiter-mass planets.
Planet formation theories predict that some planets may be ejected from their parent systems as result of dynamical interactions and other processes. Unbound planets can also be formed through gravitational collapse, in a way similar to that in which stars form. A handful of free-floating planetary-mass objects have been discovered by infrared surveys of young stellar clusters and star-forming regions as well as wide-field surveys, but these studies are incomplete for objects below five Jupiter masses. Gravitational microlensing is the only method capable of exploring the entire population of free-floating planets down to Mars-mass objects, because the microlensing signal does not depend on the brightness of the lensing object. A characteristic timescale of microlensing events depends on the mass of the lens: the less massive the lens, the shorter the microlensing event. A previous analysis of 474 microlensing events found an excess of ten very short events (1-2 days)-more than known stellar populations would suggest-indicating the existence of a large population of unbound or wide-orbit Jupiter-mass planets (reported to be almost twice as common as main-sequence stars). These results, however, do not match predictions of planet-formation theories and surveys of young clusters. Here we analyse a sample of microlensing events six times larger than that of ref. 11 discovered during the years 2010-15. Although our survey has very high sensitivity (detection efficiency) to short-timescale (1-2 days) microlensing events, we found no excess of events with timescales in this range, with a 95 per cent upper limit on the frequency of Jupiter-mass free-floating or wide-orbit planets of 0.25 planets per main-sequence star. We detected a few possible ultrashort-timescale events (with timescales of less than half a day), which may indicate the existence of Earth-mass and super-Earth-mass free-floating planets, as predicted by planet-formation theories.


Social Media Interventions for Nutrition Education Among Adolescents: Scoping Review.
Adolescence is a critical period for reinforcing healthy dietary behaviors and supporting the development of cooking skills. Social media may be an avenue for supporting these behaviors, as it is popular among adolescents and can improve access to nutrition education interventions. This study sought to understand the optimal implementation of effective social media-based nutrition education interventions to inform the implementation of future social media-based nutrition education interventions. A scoping review of the characteristics, feasibility, effectiveness, and factors influencing social media-based nutrition education interventions for adolescents was conducted. We searched MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO databases using a predefined search strategy. Primary research articles were independently screened and included if they involved adolescent populations (10-18 years old) and delivered nutrition education through social media. The information on intervention characteristics, feasibility, effectiveness, and factors influencing social media-based nutrition education interventions was extracted. A total of 28 publications out of 20,557 met the eligibility criteria. Twenty-five nutrition interventions were examined by 28 studies. Fourteen interventions used homegrown social media platforms, 8 used Facebook, and 2 used Instagram. Feasibility outcomes were infrequently reported, and the cost of intervention delivery was not reported. Engagement with interventions was variable; high engagement was not required to elicit significant improvements in dietary behaviors. Tailoring interventions, offering practical content, meaningful peer support, and involving families and communities facilitated successful interventions. Strategies to address engagement and technical issues were varied. Emerging evidence demonstrates that social media interventions for adolescent nutrition are acceptable and improve nutrition outcomes. Future interventions should strengthen peer support components and tailor delivery to specific populations. Further research should examine engagement, adherence, and the impact of interventions on behavioral and physical outcomes. This review is the first to examine the use of social media as the primary medium for nutrition education for adolescent populations. The analysis used in this review argues the importance of peer support in social media-based nutrition interventions and the need for user-centered design of the interventions.


Application of wavelet transform for PDZ domain classification.
PDZ domains have been identified as part of an array of signaling proteins that are often unrelated, except for the well-conserved structural PDZ domain they contain. These domains have been linked to many disease processes including common Avian influenza, as well as very rare conditions such as Fraser and Usher syndromes. Historically, based on the interactions and the nature of bonds they form, PDZ domains have most often been classified into one of three classes (class I, class II and others - class III), that is directly dependent on their binding partner. In this study, we report on three unique feature extraction approaches based on the bigram and trigram occurrence and existence rearrangements within the domain's primary amino acid sequences in assisting PDZ domain classification. Wavelet packet transform (WPT) and Shannon entropy denoted by wavelet entropy (WE) feature extraction methods were proposed. Using 115 unique human and mouse PDZ domains, the existence rearrangement approach yielded a high recognition rate (78.34%), which outperformed our occurrence rearrangements based method. The recognition rate was (81.41%) with validation technique. The method reported for PDZ domain classification from primary sequences proved to be an encouraging approach for obtaining consistent classification results. We anticipate that by increasing the database size, we can further improve feature extraction and correct classification.


[Correction of secondary hyperlipidemia in children with diabetes].
At 25 children with insulin dependent diabetes mellitus (IDDM, Type I) in a decompensation stage was estimated efficiency of correction secondary hyperlipidemia. The basic group (n = 11) along with insulinotherapy and a lipotrophic preparation (methionine) accepted probiotic Bifiform Baby in a dose 0.5 g once a day within 10 days; the comparison group (n = 14) received insulin therapy and a lipotrophic preparation. Efficiency of treatment was estimated on dynamics of lipids in serum of blood: triglycerides (TG), the total cholesterol (TH), betalipoproteides (BLP). At patients of the basic group authentic decrease TG, TH, BLP was established; at patients of group of comparison--decrease TH and BLP. Advantage of therapy secondary hyperlipidemia at children with diabetic ketoacidosis with use of Bifiform Baby consists in the elimination of the main infringement of a metabolismus of lipids in the given disease--hypertriglyceridemia.


Spontaneous uterine rupture during pregnancy: case report and review of literature.
Rupture of a gravid uterus is a surgical emergency. Predisposing factors include a scarred uterus. Spontaneous rupture of an unscarred uterus during pregnancy is a rare occurrence. We hereby present the case of a spontaneous complete uterine rupture at a gestational age of 34 weeks in a 35 year old patient. The case was managed at the University Teaching Hospital of Yaounde (Cameroon). She had past history of two uterine curettages. She presented with abdominal pain of sudden onset. After ultrasound scan, uterine rupture was diagnosed and an emergency laparotomy done. The entire amniotic sac was found in the peritoneal cavity with a rupture of the uterine fundus. Spontaneous uterine rupture occurs when there is an upper segment uterine scar. This case report shows that past history of curettage is a risk factor for the presence of uterine scar.


Comparison of the 'Denver regimen' against acute tuberculosis in the mouse and guinea pig.
In this study, we sought to compare the sterilizing activity of human-equivalent doses of the 'Denver regimen' against acute tuberculosis (TB) infection in the standard mouse model and in the guinea pig. Pharmacokinetic studies in guinea pigs were used to establish human-equivalent doses for rifampicin, isoniazid and pyrazinamide. Guinea pigs and mice were aerosol-infected with Mycobacterium tuberculosis CDC1551 and treatment was started 2 weeks later with rifampicin/isoniazid/pyrazinamide for up to 6 months. For the first 2 weeks of therapy, the dosing frequency was 5 days/week, and for the remaining period, twice weekly. Treatment was discontinued in groups of 30 mice and 10 guinea pigs at 5 months and at 6 months, and these animals were held for a further 3 months in order to assess relapse rates. Guinea pig lungs became culture-negative after 3 months of predominantly twice-weekly treatment and relapse rates were 0% (0/10) both after 5 months and after 6 months of treatment. In contrast, all mice remained culture-positive despite 6 months of the same treatment, and 93% (28/30) and 69% (20/29) of mice relapsed after treatment for 5 and 6 months, respectively. Treatment with rifampicin/isoniazid/pyrazinamide administered at human-equivalent doses is much more potent against acute TB infection in guinea pigs than in mice. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence.


Evolutionary changes in defensive specialized metabolism in the genus Hordeum.
Plants have developed defensive specialized metabolites over the course of evolution. In the genus Hordeum, which includes the important cereal crop barley, specialized metabolites such as hordatines, benzoxazinones, and gramine have been identified. Hordeum species are classified into four clades, H, Xu, Xa, and I. The presence or absence of defensive specialized metabolites was analyzed in representative Hordeum species that included all of the four clades. In the H clade, Hordeum vulgare accumulated hordatines but not benzoxazinones, whereas H. bulbosum accumulated neither compound. Some accessions in the H clade accumulated gramine. Species in the clades I and Xa accumulated benzoxazinones without hordatines. In H. murinum, a Xu clade species, neither hordatines nor benzoxazinones were detected. Two hitherto undescribed compounds were found to commonly accumulate in H. bulbosum in the H clade and H. murinum in the Xu clade. On the basis of spectroscopic analyses, they were identified as dehydrodimers of feruloylagmatine and were designated murinamides A and B. Radical coupling reactions with feruloylagmatine as a substrate by peroxidase afforded murinamides A and B. These compounds showed antifungal activities against Bipolaris sorokiniana and Fusarium asiaticum, indicating their defensive roles. Because hordatines are also dehydrodimers of hydroxycinnamic acid amides (HCAAs) of agmatine, both the H and Xu clade species are considered to accumulate the same class of compounds. Thus, when the H/Xu clades split from the I/Xa clades during evolution, the defensive metabolites shifted from benzoxazinones to dehydrodimers of agmatine HCAAs plus gramine in the H/Xu clades.


Active Redesign of a Medicaid Care Management Strategy for Greater Return on Investment: Predicting Impactability.
Care management of high-cost/high-needs patients is an increasingly common strategy to reduce health care costs. A variety of targeting methodologies have emerged to identify patients with high historical or predicted health care utilization, but the more pertinent question for program planners is how to identify those who are most likely to benefit from care management intervention. This paper describes the evolution of complex care management targeting strategies in Community Care of North Carolina's (CCNC) work with the statewide non-dual Medicaid population, culminating in the development of an "Impactability Score" that uses administrative data to predict achievable savings. It describes CCNC's pragmatic approach for estimating intervention effects in a historical cohort of 23,455 individuals, using a control population of 14,839 to determine expected spending at an individual level, against which actual spending could be compared. The actual-to-expected spending difference was then used as the dependent variable in a multivariate model to determine the predictive contribution of a multitude of demographic, clinical, and utilization characteristics. The coefficients from this model yielded the information required to build predictive models for prospective use. Model variables related to medication adherence and historical utilization unexplained by disease burden proved to be more important predictors of impactability than any given diagnosis or event, disease profile, or overall costs of care. Comparison of this approach to alternative targeting strategies (emergency department super-utilizers, inpatient super-utilizers, or patients with highest Hierarchical Condition Category risk scores) suggests a 2- to 3-fold higher return on investment using impactability-based targeting.


Single Bone Fixation versus Both Bone Fixation for Pediatric Unstable Forearm Fractures: A Systematic Review and Metaanalysis.
It is uncertain whether single bone fixation is comparable to both bone fixation in the treatment of unstable both bone forearm fractures in children. A systematic review using PubMed, Embase, and Cochrane Library database searches was performed on October 1, 2015 on English language scientific literature only. Clinical study designs comparing single bone fixation with both bone fixation of pediatric both bone forearm fractures were included. Studies of only one treatment modality were excluded from the study. Studies eligible for inclusion were assessed using the risk of bias tool for nonrandomized studies. Metaanalysis points to no significant differences in re-angulation, loss of rotation, union time and complications between single bone and both bone fixation. However, the published research lacks quality. Despite scattered evidence and small sample sizes, the metaanalysis suggests single bone fixation can be considered a suitable alternative for both bone forearm fractures in children, as it carries less time in surgery and less cost without compromise in final functional outcome compared to double-bone fixation.


Transcriptomic studies of the airway field of injury associated with smoking-related lung disease.
The "field of injury" hypothesis proposes that exposure to an inhaled insult such as cigarette smoke elicits a common molecular response throughout the respiratory tract. This response can therefore be quantified in any airway tissue, including readily accessible epithelial cells in the bronchus, nose, and mouth. High-throughput technologies, such as whole-genome gene expression microarrays, can be employed to catalog the physiological consequences of such exposures in the airway epithelium. Pulmonary diseases such as chronic obstructive pulmonary disease, lung cancer, and asthma are also thought to be associated with a field of injury, and in patients with these diseases, airway epithelial cells can be a useful surrogate for diseased tissue that is often difficult to obtain. Global measurement of mRNA and microRNA expression in these cells can provide useful information about the molecular pathogenesis of such diseases and may be useful for diagnosis and for predicting prognosis and response to therapy. In this review, our aim is to summarize the history and state of the art of such "transcriptomic" studies in the human airway epithelium, especially in smoking and smoking-related lung diseases, and to highlight future directions for this field.


Na+-H+ exchange and Na+ entry across the apical membrane of Necturus gallbladder.
The role of Na+-H+ exchange in Na+ transport across the apical membrane was evaluated in Necturus gallbladder epithelium by means of intracellular Na+ activity (aNai) and 22Na+ uptake measurements. Under control conditions, complete replacement of Na+ in the mucosal solution with tetramethylammonium reduced aNai from 14.0 to 6.9 mM in 2 min (P less than 0.001). Mucosal addition of the Na+-H+ exchange inhibitor amiloride (10(-3) M) reduced aNai from 15.0 to 13.3 mM (P less than 0.001), whereas bumetanide (10(-5) and 10(-4) M) had no effect. Na+ influx across the apical membrane was studied by treating the tissues with ouabain, bathing them in Na-free solutions, and suddenly replacing the mucosal solution with an Na-containing solution. When the mucosal solution was replaced with Na-Ringer's, aNai increased at approximately 11 mM/min. This increase was inhibited by 54% by amiloride (10(-3) M, P less than 0.001) and was unaffected by bumetanide (10(-5) M). Amiloride-inhibitable Na+ fluxes across the apical membrane were also induced by the imposition of pH gradients. Na+ influx was also examined in tissues that had not been treated with ouabain. Under control conditions, 22Na+ influx from the mucosal solution into the epithelium was linear over the first 60 s and was inhibited by 40% by amiloride (10(-3) M, P less than 0.001) and by 19% by bumetanide (10(-5) M, P less than 0.025). We conclude that Na+-H+ exchange is a major pathway for Na+ entry in Necturus gallbladder, which accounts for at least half of apical Na+ influx both under transporting conditions and during exposure to ouabain. Bumetanide-inhibitable Na+ entry mechanisms may account for only a smaller fraction of Na+ influx under transporting conditions, and cannot explain influx in ouabain-treated tissues. These results support the hypothesis that NaCl entry results primarily from the operation of parallel Na+-H+ and Cl--HCO-3 exchangers, and not from a bumetanide-inhibitable NaCl cotransporter.


Endoscopic retrograde cholangiopancreatography in pancreatic and biliary tract disease in Korean children.
To assess the indications, findings, therapeutic procedures, safety, and complications of endoscopic retrograde cholangiopancreatography (ERCP) performed in Korean children. The demographic characteristics, indications for ERCP, findings, therapeutic procedures, and complications of 122 pediatric patients who underwent 245 ERCPs in the Asan Medical Center between June 1994 and March 2008 were investigated. The mean age of the 122 patients was 8.0 +/- 4.2 years. Indications were biliary pathology in 78 (64.0%), pancreatic pathology in 43 (35.2%), and chronic abdominal pain in one. Biliary indications included choledochal cysts in 40, choledocholithiasis in 24, suspected sclerosing cholangitis in 8, trauma in 2, and other conditions in 4. Pancreatic indications included acute pancreatitis in 7, acute recurrent pancreatitis in 11, chronic pancreatitis in 20, trauma in 3, and pancreatic mass in 2. Of the 245 ERCPs, success rate was 98.4% and 190 (77.6%) were for therapeutic purposes, including endoscopic nasal drainage (51.8%), biliary sphincterotomy (38.0%), pancreatic sphincterotomy (23.3%), stent insertion (15.1%), stone extraction (18.8%), and balloon dilatation (11.0%). Complications were post-ERCP pancreatitis in 16 (6.5%), ileus in 23 (9.4%), hemorrhage in 2 (0.8%), perforation in 2 (0.8%), sepsis in 1 (0.4%), and impacted basket in 1 (0.4%). There were no procedure-related deaths, and most complications improved under supportive care. This study showed that there is a high incidence of choledochal cyst and diagnostic and therapeutic ERCP for the management of various biliary and pancreatic diseases was safe and effective in Korean children.


HPLC/MS(N) analysis of retinoids.
This protocol describes a highly sensitive and selective method to quantify retinoids using normal-phase HPLC with online APCI MS(N). The retinoids are key regulators of gene expression, retinol being oxidized via a retinaldehyde intermediate to retinoic acid (RA) which activates specific nuclear receptors, the signalling of which is turned off by oxidative inactivation of the ligand to 4-oxo-RA and other metabolites. Many of these retinoids are present only transiently at low concentrations in tissues and during analysis are labile to heat, light, and oxygen. HPLC with online APCI MS(N) provides a rapid technique to quantify these retinoids simultaneously. Techniques to extract the retinoids and prevent their degradation are described, with an emphasis on transcriptionally active RA. RA controls patterning of gene expression in the embryo, organizing embryonic morphology in the central nervous system. Similarly, a patterned distribution of RA controls function of the adult CNS, a tissue particularly difficult to analyse for RA because of its high lipid content. To understand how these patterns are organized in the brain and change over time, it is essential to determine the concentration of RA in small areas of tissues, and techniques of exquisite sensitivity are indispensable.


Experimental transmission of Sarcocystis muris (Apicomplexa: Sarcocystidae) sporocysts from a naturally infected cat (Felis catus) to immunocompetent and immunocompromised mice.
Cats serve as definitive hosts for zoonotic Toxoplasma gondii , a protozoan that threatens human reproductive health, but they also excrete sporocysts of related protozoan that pose no known human health risk. Here we provide the first definitive evidence for natural infection with the enzootic parasite Sarcocystis muris, one such enzootic parasite. Sporulated Sarcocystis sp. sporocysts were found in rectal contents of an adult feral cat ( Felis catus ) in Giza, Egypt. After these sporocysts were orally inoculated into 2 Swiss Webster mice, sarcocysts were found to have developed in skeletal muscles 114 days later. As observed through transmission electron microscopy, the cyst wall corresponded to Type 1, and the parasitophorous vacuolar membrane had tiny outpocketing of blebs (<200 nm thick) that were not invaginated into the interior of the cyst; these structures were identical to the sarcocyst wall described for a Costa Rican isolate of S. muris that has served as an experimental model for nearly 4 decades. Two parasite-free cats fed sarcocyst-infected muscles developed patent infections; fully sporulated sporocysts (10-11 × 7.0 μm) were found in the lamina propria of small intestines of cats killed 6 and 7 days postinoculation (PI). Interferon gamma gene knockout (KO) mice were orally inoculated with sporocysts from experimentally infected cats, and their tissues were examined histologically; sarcocysts were found in 5 KO mice killed 87, 115, 196, 196, 196 days PI, but no stages were seen in 5 KO mice 10, 14, 14, 18, and 39 days PI. Bradyzoites were released from intramuscular sarcocysts of a KO mouse killed 115 days PI and orally inoculated into 5 KO mice. No stage of Sarcocystis was found in any organ (including intestinal lamina propria) of KO mice killed 4, 8, 81, 190, and 190 days PI, confirming that the definitive host is required to complete the life cycle even in the case of immunodeficient mice. This is the first confirmation of S. muris infection in a naturally infected cat anywhere.


Potent natural soluble epoxide hydrolase inhibitors from Pentadiplandra brazzeana baillon: synthesis, quantification, and measurement of biological activities in vitro and in vivo.
We describe here three urea-based soluble epoxide hydrolase (sEH) inhibitors from the root of the plant Pentadiplandra brazzeana. The concentration of these ureas in the root was quantified by LC-MS/MS, showing that 1, 3-bis (4-methoxybenzyl) urea (MMU) is the most abundant (42.3 μg/g dry root weight). All of the ureas were chemically synthesized, and their inhibitory activity toward recombinant human and recombinant rat sEH was measured. The most potent compound, MMU, showed an IC50 of 92 nM via fluorescent assay and a Ki of 54 nM via radioactivity-based assay on human sEH. MMU effectively reduced inflammatory pain in a rat nociceptive pain assay. These compounds are among the most potent sEH inhibitors derived from natural sources. Moreover, inhibition of sEH by these compounds may mechanistically explain some of the therapeutic effects of P. brazzeana.


Dystonic tremor caused by mutation of the glucose transporter gene GLUT1.
Glucose transporter 1 deficiency syndrome (GLUT1-DS) is due to heterozygous mutation of the glucose transporter type 1 gene (GLUT1/SLC2A1). GLUT1-DS is characterized by movement disorders, including paroxysmal exercise-induced dystonia (PED), as well as seizures, mental retardation and hypoglycorrhachia. Tremor was recently shown to be part of the phenotype, but its clinical and electrophysiological features have not yet been described in detail, and GLUT1 tremor reports are rare. We describe two patients, a young woman and her mother, who were referred to us for tremor. We also systematically review published cases of GLUT1-DS with tremor (14 cases, including ours), focusing on clinical features. In most cases (10/14), the tremor, which involved the limbs and voice, fulfilled clinical criteria for dystonic tremor (DT), occurring in body areas affected by dystonia. Tremor was the only permanent symptom in 2 cases. Recordings, reported here for the first time, showed an irregular 6- to 8.5-Hz tremor compatible with DT in our two patients. These findings show that tremor, and particularly DT, may be a presenting symptom of GLUT1-DS. Patients who present with dystonic tremor, with or without mental retardation, seizures, movement disorders and/or a family history, should therefore be screened for GLUT1-DS.


Genetic Approach to Elucidate the Role of Cyclophilin D in Traumatic Brain Injury Pathology.
Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the current understanding of the role CypD plays in TBI pathobiology. Further, we directly assessed the role of CypD in mediating cell death following TBI by utilizing mice lacking the CypD encoding gene Ppif. Following controlled cortical impact (CCI), the genetic knockout of CypD protected acute mitochondrial bioenergetics at 6 h post-injury and reduced subacute cortical tissue and hippocampal cell loss at 18 d post-injury. The administration of CsA following experimental TBI in Ppif-/- mice improved cortical tissue sparing, highlighting the multiple cellular targets of CsA in the mitigation of TBI pathology. The loss of CypD appeared to desensitize the mitochondrial response to calcium burden induced by TBI; this maintenance of mitochondrial function underlies the observed neuroprotective effect of the CypD knockout. These studies highlight the importance of maintaining mitochondrial homeostasis after injury and validate CypD as a therapeutic target for TBI. Further, these results solidify the beneficial effects of CsA treatment following TBI.


Cross-Sectional Study of U.S. Interns' Perceptions of Clinical Nutrition Education.
Background Medical students have historically perceived a lack of training in clinical nutrition. Rapid advances in medical science have compelled significant changes in medical education pedagogy. It is unclear what effect this has had on student's perceptions. Objective To assess interns' perception of clinical nutrition education during medical school. Design A cross-sectional survey of medical, surgical, and obstetric interns from 6 academic hospitals across the United States during the middle of their first year in November of 2010 (n = 289). Bivariate analysis and logistic regression was used to describe interns' perceptions and evaluate for factors that determined these perceptions. Results A total of 122 interns responded to the survey, for a response rate of 42%. These interns represented 72 different medical schools. Only 29% of interns reported they had been sufficiently trained in nutrition. On average, interns who reported being prepared reported a mean of 4 ± 3.4 weeks of training during medical school, while unprepared interns reported a mean of 2 ± 2.6 weeks of training (P = .02). Interns with prior graduate training in nutrition (n = 18) almost exclusively reported that medical school training was insufficient (94%, P = .02). After adjusting for age, gender, internship, undergraduate training, and being a foreign graduate, only the number of weeks of training remained significantly associated with perceived preparation (P = .03). Conclusion Most interns in medicine, surgery, and obstetrics feel unprepared to handle cases requiring knowledge of clinical nutrition. Interns feel that medical school is not adequately preparing them for the needs of clinical practice.


ST-segment elevation in patients with cocaine abuse and chest pain.
Use of cocaine may complicate the diagnosis of myocardial infarction (MI) and may influence treatment strategy. Patients with symptoms suggestive of acute coronary syndrome (ACS) should be questioned about the use of cocaine. Initial management of cocaine users presenting with chest pain and ST segment elevation should include administration of glyceryl trinitrate (GTN). Assessment for resolution of chest discomfort and ECG changes should be undertaken before fibrinolytic therapy or angiography is considered. We present a case of patient with chest pain (CP) and ST elevation after cocaine use, whose symptoms and ST changes promptly resolved after medical therapy. Our case highlights the importance of medical therapy in patient with CP and ST elevation after cocaine abuse, before activating cardiac catheterization laboratory for emergent angiography.


Tollip coordinates Parkin-dependent trafficking of mitochondrial-derived vesicles.
Multiple mitochondrial quality control pathways exist to maintain the health of mitochondria and ensure cell homeostasis. Here, we investigate the role of the endosomal adaptor Tollip during the mitochondrial stress response and identify its interaction and colocalisation with the Parkinson's disease-associated E3 ubiquitin ligase Parkin. The interaction between Tollip and Parkin is dependent on the ubiquitin-binding CUE domain of Tollip, but independent of Tom1 and mitophagy. Interestingly, this interaction is independent of Parkin mitochondrial recruitment and ligase activity but requires an intact ubiquitin-like (UBL) domain. Importantly, Tollip regulates Parkin-dependent endosomal trafficking of a discrete subset of mitochondrial-derived vesicles (MDVs) to facilitate delivery to lysosomes. Retromer function and an interaction with Tom1 allow Tollip to facilitate late endosome/lysosome trafficking in response to mitochondrial stress. We find that upregulation of TOM20-positive MDVs upon mitochondrial stress requires Tollip interaction with ubiquitin, endosomal membranes and Tom1 to ensure their trafficking to the lysosomes. Thus, we conclude that Tollip, via an association with Parkin, is an essential coordinator to sort damaged mitochondrial-derived cargo to the lysosomes.


Psychometric properties of the EQ-5D-5L: a systematic review of the literature.
Although the EQ-5D has a long history of use in a wide range of populations, the newer five-level version (EQ-5D-5L) has not yet had such extensive experience. This systematic review summarizes the available published scientific evidence on the psychometric properties of the EQ-5D-5L. Pre-determined key words and exclusion criteria were used to systematically search publications from 2011 to 2019. Information on study characteristics and psychometric properties were extracted: specifically, EQ-5D-5L distribution (including ceiling and floor), missing values, reliability (test-retest), validity (convergent, known-groups, discriminate) and responsiveness (distribution, anchor-based). EQ-5D-5L index value means, ceiling and correlation coefficients (convergent validity) were pooled across the studies using random-effects models. Of the 889 identified publications, 99 were included for review, representing 32 countries. Musculoskeletal/orthopedic problems and cancer (n = 8 each) were most often studied. Most papers found missing values (17 of 17 papers) and floor effects (43 of 48 papers) to be unproblematic. While the index was found to be reliable (9 of 9 papers), individual dimensions exhibited instability over time. Index values and dimensions demonstrated moderate to strong correlations with global health measures, other multi-attribute utility instruments, physical/functional health, pain, activities of daily living, and clinical/biological measures. The instrument was not correlated with life satisfaction and cognition/communication measures. Responsiveness was addressed by 15 studies, finding moderate effect sizes when confined to studied subgroups with improvements in health. The EQ-5D-5L exhibits excellent psychometric properties across a broad range of populations, conditions and settings. Rigorous exploration of its responsiveness is needed.


Remote sensing of ocean currents.
A method of remotely measuring near-surface ocean currents with a synthetic aperture radar (SAR) is described. The apparatus consists of a single SAR transmitter and two receiving antennas. The phase difference between SAR image scenes obtained from the antennas forms an interferogram that is directly proportional to the surface current. The first field test of this technique against conventional measurements gives estimates of mean currents accurate to order 20 percent, that is, root-mean-square errors of 5 to 10 centimeters per second in mean flows of 27 to 56 centimeters per second. If the full potential of the method could be realized with spacecraft, then it might be possible to routinely monitor the surface currents of the world's oceans.


Extension of conserved regions in the rat and mouse genomes by chromosomal assignments of 29 rat genes.
We recently constructed a comparative genetic map of the rat, mouse and human genomes based on information obtained from several databases. In this study, we performed chromosomal assignments of 29 rat genes with somatic cell hybrid clones, in order to clarify and extend the conserved regions in the rat and mouse genomes. As a result, the conserved regions were extended by 89 cM. Together with our previous report, the length of the conserved regions in the rat and mouse spans 847 cM on the mouse linkage map, indicating that 53% of the mouse genome is covered by homologous regions in the rat. In addition, four conserved regions were newly revealed. The method described in this study appears to be simple and efficient for constructing a whole genome comparative map of the rat and mouse.


[Chemical modification of phenylalanyl-tRNA synthetase and ribosomes of Escherichia coli with derivatives of tRNA-Phe carrying photoreactive groups on guanosine residues].
Photoreactive derivatives of tRNAPhe (E. coli) were synthesized by alkylation of the tRNAPhe with 4-(N-2-chloroethyl-N-methylamino)benzylamine and subsequent treatment with 1.4--dinitro-5-fluorophenylazide. The derivatives are active in binding with ribosomes and phenylalanyl-tRNA synthetase when the extent of modification is lower than 3 reactive groups per tRNAPhe molecule. Under irradiation the derivatives modify exclusively the beta-subunit of the phenylalanyl-tRNA synthetase.


Immunotherapy for advanced urothelial carcinoma (UC): rational and current evidence.
Combination platinum-based chemotherapy has been the standard of care for several decades in first-line treatment of advanced urothelial carcinoma (UC) patients. UC is often chemosensitive, though durable responses are quite rare and the development of chemoresistance still leads to poor clinical outcomes. Up until a few years ago, UC patients could not benefit from any valuable alternatives to cytotoxic chemotherapy, but the scenario has been recently transformed by the advent of immunotherapy. Molecular biology of UC is characterised by a relatively high prevalence of alterations in DNA damage response pathway, genomic instability, high tumour burden, and elevated programmed cell death ligand 1 (PD-L1) protein expression, which are established factors predicting favourable response to immune checkpoint inhibitors (ICIs) in several tumour types. To date, various ICIs have been approved as systemic anti-cancer therapy for advanced UC in multiple settings, including first-line, maintenance, and second-line therapy. ICIs are also in development either as monotherapy or in combination with chemotherapy or other targeted agents. Moreover, a number of alternative ICIs, interleukins, and novel immune molecules have been identified as promising agents in advanced UC. Herein, we review rational and current literature evidence supporting the clinical development and current indications of immunotherapy, particularly focusing on ICIs.


Image Gently: progress and challenges in CT education and advocacy.
Significant progress has been made in radiation protection for children during the last 10 years. This includes increased awareness of the need for radiation protection for pediatric patients with international partnerships through the Alliance for Radiation Safety in Pediatric Imaging. This paper identifies five areas of significant progress in radiation safety for children: the growth of the Alliance; the development of an adult radiation protection campaign Image Wisely™; increased collaboration with government agencies, societies and the vendor community; the development of national guidelines in pediatric nuclear medicine, and the development of a size-based patient dose correction factor by the American Association of Physicists in Medicine, Task Group 204. However, many challenges remain. These include the need for continued education and change of practice at adult-focused hospitals where many pediatric CT exams are performed; the need for increased emphasis on appropriateness of pediatric imaging and outcomes research to validate the performance of CT studies, and the advancement of the work of the first pediatric national dose registry to determine the "state of the practice" with the final goal of establishing ranges of optimal CT technique for specific scan indications when imaging children with CT.


Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons.
The disease mechanism of Rett syndrome (RTT) is not well understood. Studies in RTT mouse models have suggested a non-cell-autonomous role for astrocytes in RTT pathogenesis. However, it is not clear whether this is also true for human RTT astrocytes. To establish an in vitro human RTT model, we previously generated isogenic induced pluripotent stem cell (iPSC) lines from several RTT patients carrying different disease-causing mutations. Here, we show that these RTT iPSC lines can be efficiently differentiated into astroglial progenitors and glial fibrillary acidic protein-expressing (GFAP(+)) astrocytes that maintain isogenic status, that mutant RTT astrocytes carrying three different RTT mutations and their conditioned media have adverse effects on the morphology and function of wild-type neurons and that the glial effect on neuronal morphology is independent of the intrinsic neuronal deficit in mutant neurons. Moreover, we show that both insulin-like growth factor 1 (IGF-1) and GPE (a peptide containing the first 3 amino acids of IGF-1) are able to partially rescue the neuronal deficits caused by mutant RTT astrocytes. Our findings confirm the critical glial contribution to RTT pathology, reveal potential cellular targets of IGF-1 therapy and further validate patient-specific iPSCs and their derivatives as valuable tools to study RTT disease mechanism.


Biotransformation and pharmacokinetics in the rhesus monkey of 2-n-propyl-4-pentenoic acid, a toxic metabolite of valproic acid.
2-n-Propyl-4-pentenoic acid (delta 4-VPA), a hepatotoxic metabolite of valproic acid (VPA), was administered by iv bolus injection (14 mg kg-1) to two adult male rhesus monkeys. The plasma concentration vs. time curve for delta 4-VPA in these animals was biexponential and the effective half-life values were 0.53 and 0.67 hr. The pharmacokinetic profile of delta 4-VPA was similar to that of VPA in the monkey, although the unbound fraction of delta 4-VPA in plasma was approximately 2.5-fold greater than the value for the parent drug. The major route of elimination of delta 4-VPA was excretion into urine, and studies with a group of eight animals indicated that delta 4-VPA undergoes extensive biotransformation in this species. A total of 20 metabolites was detected in urine by GC-MS techniques, and 19 of these were identified positively by comparison of their gas-liquid chromatographic and mass spectrometric properties with those of the authentic compounds prepared by synthesis. Many of these metabolites were present largely in the form of glucuronide conjugates, as was delta 4-VPA itself. The major pathways of metabolism of delta 4-VPA were found to be ester glucuronide formation and beta-oxidation, whereas omega- and (omega-1)-oxidation processes were of minor quantitative importance. Excretion of unchanged drug and its metabolites into urine over 24 hr accounted collectively for some 59% of the administered dose, a figure which was appreciably less than the corresponding recovery of metabolites of VPA in the same monkeys. The possibility is raised that beta-oxidation of delta 4-VPA leads to the generation of a chemically reactive intermediate(s) which alkylate(s) cellular macromolecules and thereby forms tissue-bound residues. The significance of such a phenomenon is discussed in relation to the etiology of VPA-induced liver injury.


[Kinetic model of the gating system of the sodium channel in a Ranvier node membrane].
A kinetic model of the sodium channel gating system consisting of four subunits with three states--closed (X), open (Y) and inactivated (Z)--is proposed. For the channel to conduct, all the four subunits must be in the open state. The transitions between states X and Y are independent, while those between states X and Z are coupled, so that for the particle considered transition of one of two neighbouring particles into state Z increases the activation energy of the step by kT. The model fits rather well to the experimental data.


Histopathological aspects and staging systems in non-traumatic femoral head osteonecrosis: an overview of the literature.
The pathogenesis of non traumatic osteonecrosis of the femoral head (ONFH) has not yet been established. The literature shows a variable nomenclatura for this condition that often leads to confusion. Several risk factors have been identified but histopathological and radiological outcomes are common. To provide the overview on the current knowledges about the nomenclatura, etiology, disease progression, relationship between histopathological changes and imaging techniques in order to stage the disease accurately. Etiology and pathogenesis: Genetic predisposition, metabolic factors, local factors affecting blood supply such as vascular damage, increased intraosseous pressure and mechanical stress are involved in this desease. The final results are bone ischemia and infarction getting bone deathand FH collapse. Histopathological aspects and staging systems: Several staging systems have been developed to stage ONFH based on imaging techniques.The subchondral collapse, the size or quantification of the lesion, and the lesion location within the femoral head are identified as the most important prognostic factors in ONFH disease. Histological analysis plays a critical role to evaluate the quality of necrotic area and the differences between microscopic, macroscopic and imaging outcomes were detected. an ideal staging system is necessary to stage ONFH desease to detect several aspects, but itìs more difficult to create. At the present time we summarize some aspects that are advisable to focus during ONFH for the correct treatment.


Co-occurring ripple oscillations facilitate neuronal interactions between cortical locations in humans.
Synchronous bursts of high frequency oscillations ('ripples') are hypothesized to contribute to binding by facilitating integration of neuronal firing across cortical locations. We tested this hypothesis using local field-potentials and single-unit firing from four 96-channel microelectrode arrays in supragranular cortex of 3 patients. Neurons in co-rippling locations showed increased short-latency co-firing, prediction of each-other's firing, and co-participation in neural assemblies. Effects were similar for putative pyramidal and interneurons, during NREM sleep and waking, in temporal and Rolandic cortices, and at distances up to 16mm. Increased co-prediction during co-ripples was maintained when firing-rate changes were equated, and were strongly modulated by ripple phase. Co-ripple enhanced prediction is reciprocal, synergistic with local upstates, and further enhanced when multiple sites co-ripple. Together, these results support the hypothesis that trans-cortical co-ripples increase the integration of neuronal firing of neurons in different cortical locations, and do so in part through phase-modulation rather than unstructured activation.


Frequency of sleep apnea in stroke and TIA patients: a meta-analysis.
To determine the frequency of sleep disordered breathing (SDB) in ischemic and hemorrhagic stroke and transient ischemic attack (TIA) patients by meta-analysis. A systematic literature search using Medline, EMBASE and CINAHL and a manual review of references through December 2008 was conducted using specific search terms. The frequency of SDB stratified by apnea hypopnea index (AHI) was extracted by the author. Weighted averages using a random-effects model are reported with 95% confidence intervals. Twenty-nine articles evaluating patients with autoCPAP, limited-channel sleep study, or full polysomnography were included in this study. In meta-analysis of 2,343 ischemic or hemorrhagic stroke and TIA patients, the frequency of SDB with AHI > 5 was 72% and with AHI > 20 was 38%. Only 7% of the SDB was primarily central apnea. There was no significant difference in SDB prevalence by event type, timing after stroke, or type of monitoring. Males had a higher percentage of SDB (AHI > 10) than females (65% compared to 48% p = 0.001). Patients with recurrent strokes had a higher percentage of SDB (AHI > 10) than initial strokes (74% compared to 57% p = 0.013). Patients with unknown etiology of stroke had a higher and cardioembolic etiology a lower percentage of SDB than other etiologies. SDB is very common in stroke patients irrespective of type of stroke or timing after stroke and is typically obstructive in nature. Since clinical history alone does not identify many patients with SDB, sleep studies should be considered in all stroke and TIA patients.


[Characteristics of the ultraslow activity and temperature of the brain as affected by neurotropic substances].
It has been demonstrated in experiments on rabbits with golden electrodes and thermocouples implanted to the brain that ethimizol (1.5 mg/kg) and 1-ethyl-4,5-di-(N.-methylcarbamoyl)-pyrazole (IEM-476, 3 mg/kg) altered the amplitude and frequency of ultraslow wave potentials and decreased the temperature of the hypothalamus, dorsal hippocamp and neocortex. Allylnorantifein (1-allyl-4,5-di-(N-methylcarbamoyl)-imidazole, 3 mg/kg) and 1-allyl-4,5-di-(N-methylcarbamoyl)-pyrazole (IEM-474, 3 mg/kg) altered the amplitude and frequency of ultraslow wave potentials of middle brain reticular formation nuclei, medial thalamic nuclei and of the neocortex, the structures of the nonspecific ascending system of the brain, and did not influence the temperature of the brain. The effects of IEM-476 and IEM-474 on the indicators under study were less powerful than those of ethimizol and allylnortifein.


Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome.
Smith-Magenis syndrome (SMS) is a mental retardation/multiple congenital anomalies disorder associated with a heterozygous approximately 4-Mb deletion in 17p11.2. Patients with SMS show variability in clinical phenotype despite a common deletion found in >75-80% of patients. Recently, point mutations in the retinoic acid induced 1 (RAI1) gene, which lies within the SMS critical interval, were identified in three patients with many SMS features in whom no deletion was detected. It is not clear if the entire SMS phenotype can be accounted for by RAI1 haploinsufficiency, nor has the precise function of RAI1 been delineated. We report two novel RAI1 mutations, one frameshift and one nonsense allele, in nondeletion SMS patients. Comparisons of the clinical features in these two patients, three of the previously reported RAI1 point mutation cases, and the patients with a common deletion suggest that the majority of the clinical features in SMS result from RAI1 mutation, although phenotypic variability exists even among the individuals with RAI1 point mutations. Bioinformatics analyses of RAI1 and comparative genomics between human and mouse orthologues revealed a zinc finger-like plant homeo domain (PHD) at the carboxyl terminus that is conserved in the trithorax group of chromatin-based transcription regulators. These findings suggest RAI1 is involved in transcriptional control through a multi-protein complex whose function may be altered in individuals with SMS.


Evaluating real-time image reconstruction in diffuse optical tomography using physiologically realistic test data.
In diffuse optical tomography (DOT), real-time image reconstruction of oxy- and deoxy-haemoglobin changes occurring in the brain could give valuable information in clinical care settings. Although non-linear reconstruction techniques could provide more accurate results, their computational burden makes them unsuitable for real-time applications. Linear techniques can be employed under the assumption that the expected change in absorption is small. Several approaches exist, differing primarily in their handling of regularization and the noise statistics. In real experiments, it is impossible to compute the true noise statistics, because of the presence of physiological oscillations in the measured data. This is even more critical in real-time applications, where no off-line filtering and averaging can be performed to reduce the noise level. Therefore, many studies substitute the noise covariance matrix with the identity matrix. In this paper, we examined two questions: does using the noise model with realistic, imperfect data yield an improvement in image quality compared to using the identity matrix; and what is the difference in quality between online and offline reconstructions. Bespoke test data were created using a novel process through which simulated changes in absorption were added to real resting-state DOT data. A realistic multi-layer head model was used as the geometry for the reconstruction. Results validated our assumptions, highlighting the validity of computing the noise statistics from the measured data for online image reconstruction, which was performed at 2 Hz. Our results can be directly extended to a real application where real-time imaging is required.


Illness perceptions after myocardial infarction: relations to fatigue, emotional distress, and health-related quality of life.
: Health-related quality of life (HRQoL) is impaired in patients after a myocardial infarction (MI), and fatigue and depression are common health complaints among these patients. Patients' own beliefs about their illness (illness perceptions) influence health behavior and health outcomes. The aim of the present study was to examine illness perception and its association with self-reported HRQoL, fatigue, and emotional distress among patients with MI. : The sample consisted of 204 patients who had had MI and who completed the questionnaires during the first week in the hospital and 4 months after the MI. The questionnaires used were the Illness Perception Questionnaire, Multidimensional Fatigue Inventory, Hospital Anxiety and Depression Scale, and the Short Form Health Survey (SF-36). : Patient's illness perception changed over time from a more acute to a more chronic perception of illness, and beliefs in personal and treatment control of MI had decreased. Furthermore, these negative beliefs were associated with worse experiences of fatigue and lowered HRQoL. : Patients' illness perceptions influence health outcomes after an MI. Supporting MI patients in increasing their perception of personal control could be a primary nursing strategy in rehabilitation programs aimed at facilitating health behavior, decreasing experiences of fatigue, and increasing HRQoL.


A scoping review of outcomes related to orthodontic treatment measured in cleft lip and palate.
The aim of this study was to identify and summarize the outcomes measured in orthodontic studies of children with cleft lip and/or palate. The objectives were to categorize the outcomes into pre-determined domains and to explore whether any domains were under-represented. Electronic databases and grey literature were searched until December 2016 to identify all studies of orthodontic treatment interventions in children and adolescents with cleft lip and palate. Abstracts and subsequently eligible full-text articles were screened independently and in duplicate by two reviewers. All reported outcome measures were identified and categorized into six predetermined outcome domains. The search identified 833 abstracts. The majority of studies did not assess orthodontic interventions and were therefore not eligible for inclusion. Consequently, following screening 71 eligible articles were retrieved in full, of which 40 met the inclusion criteria. Morphological features of malocclusion were measured in 27 studies (68%) and adverse effects of orthodontic treatment in 10 (25%). Functional status (n=4; 10%), physical consequences of malocclusion (n=3; 7.5%), quality of life (n=3; 7.5%) and health resource utilization (n=2; 5%) were rarely considered. Relatively few studies concerning patients with cleft lip and palate focused on orthodontic interventions. Most of the identified outcomes were concerned with measuring morphological treatment-related changes and do not reflect patient perspectives.


Self-cleavage of a 71 nucleotide-long ribozyme derived from hepatitis delta virus genomic RNA.
Self-cleavage efficiency of ribozymes derived from hepatitis delta virus (HDV) has been shown to depend on the RNA structure, which in turn may be determined by the length of the considered sequences. Here we describe the construction and functional analysis of a 71 nucleotide-long RNA genomic fragment, Rz71, which carries an 18 nucleotide deletion in a very stable GC-rich stem-loop (stem IV), predicted to be present in several computer-derived secondary structure models. Rz71 is able to undergo self-cleavage under non-denaturing conditions (the t1/2 of the reaction at 37 degrees C is 3 min). The deletion, however, is not neutral, since under the same conditions the non-deleted ribozyme cleaves to 50% in less than 15 sec. Therefore, stem-loop IV seems to play a structural role, not being directly involved in the catalytic reaction, but contributing to the correct positioning of the catalytic core of the HDV ribozyme. Rz71 is the smallest self-cleaving sub-fragment of HDV genomic RNA reported so far.


Decreased plasma glutamine level and CD4+ T cell number in response to 8 wk of anaerobic training.
The purpose of the present study was to investigate the role of plasma amino acids and glutathione (GSH) on the absolute number of leukocyte and lymphocyte subpopulations in response to different training programs. Healthy untrained subjects were randomly assigned to an 8-wk aerobic (AET) or anaerobic (ANT) exercise training program. Absolute number of cell counts did not significantly change in AET, whereas a decrease of CD4+ T cell counts (P < 0.05), a fall in cells expressing CD45RA+ antigen (P < 0.05), and a marked increase in CD8+ T cell numbers (P < 0.01) were noted in ANT at the end of the training period compared with baseline values. Furthermore, ANT demonstrated a marked rise (P < 0.001) in plasma glutamate from 27.6 +/- 2.8 to 49.8 +/- 5.2 microM and a considerable reduction (P < 0.001) of the plasma glutamine pool from 713 +/- 22 to 601 +/- 30 microM after 8 wk of training. The decrease in glutamine showed a strong positive correlation to the individual loss of CD4+ T cells (r = 0.67, P < 0.001). AET demonstrated a rise (P < 0.05) in GSH from 20.7 +/- 2.5 to 28.1 +/- 1.5 nmol/mg protein at terminal examination. In conclusion, our data indicate impairment of the number and activity of CD4+ T cells in response to 8 wk of ANT, which might be linked to metabolic factors such as glutamine.


[Burnout and the health of the medical professionals: review and preventive options].
The relevance of stress on health is an increasing interest, as well as the growth of job stress in general and specifically of the medical job stress. A consequence is the rise of medical burnout. Though burnout rates can change depending on organizational contexts and specific samples, all the information indicates high rates of prevalence in the medical population. Consequences of the syndrome are wide and important, and affect mental health, physical health, quality of life and efficiency of physicians. This situation raises the need to develop programmes of prevention and intervention that help to control and to relieve such effects following the suggestions of the European Union.


Removal of feedback inhibition of delta(1)-pyrroline-5-carboxylate synthetase results in increased proline accumulation and protection of plants from osmotic stress.
The Delta(1)-pyrroline-5-carboxylate synthetase (P5CS; EC not assigned) is the rate-limiting enzyme in proline (Pro) biosynthesis in plants and is subject to feedback inhibition by Pro. It has been suggested that the feedback regulation of P5CS is lost in plants under stress conditions. We compared Pro levels in transgenic tobacco (Nicotiana tabacum) plants expressing a wild-type form of Vigna aconitifolia P5CS and a mutated form of the enzyme (P5CSF129A) whose feedback inhibition by Pro was removed by site-directed mutagenesis. Transgenic plants expressing P5CSF129A accumulated about 2-fold more Pro than the plants expressing V. aconitifolia wild-type P5CS. This difference was further increased in plants treated with 200 mM NaCl. These results demonstrated that the feedback regulation of P5CS plays a role in controlling the level of Pro in plants under both normal and stress conditions. The elevated Pro also reduced free radical levels in response to osmotic stress, as measured by malondialdehyde production, and significantly improved the ability of the transgenic seedlings to grow in medium containing up to 200 mM NaCl. These findings shed new light on the regulation of Pro biosynthesis in plants and the role of Pro in reducing oxidative stress induced by osmotic stress, in addition to its accepted role as an osmolyte.


ERP indices of working memory updating in AD/HD: differential aspects of development, subtype, and medication.
This study investigated whether children and adolescents diagnosed with the predominantly inattentive and combined subtypes of attention deficit/hyperactivity disorder (AD/HD-in and AD/HD-com, respectively) differed on psychophysiological indices of working memory updating off- and on-stimulant medication, as compared with control subjects and each other. ERPs were recorded in AD/HD and control participants during a one-back working memory task. The N100 (discrimination), P150 (selection), N300 (memory retrieval), and P450wm (updating) components after nontarget stimuli, which served to update working memory with target identity, were assessed. Premedication abnormalities were obtained for the N300 component, delayed in the child AD/HD-com group, and attenuated in the adolescent AD/HD-in group and P450wm component for all AD/HD groups, expressed as either delayed latency and/or attenuated amplitude. ERP abnormalities were predominantly ameliorated after stimulant medication. There were no psychophysiological differences between the subtypes. A general feature of the disorder relates to a deficit in the conscious updating of working memory systems with newly relevant information (P450wm), which varies with age and subtype. Children with AD/HD-com and adolescents with AD/HD-in also exhibit abnormalities in the retrieval of relevant prior memories (N300). This study indicates that AD/HD is related to abnormalities in the capacity to modulate the content of working memory stores.


Development of Biopolyesters (PHA) as Part of the Swiss Priority Program in Biotechnology.
The Swiss Priority Program in Biotechnology of the Swiss National Science Foundation that lasted between 1992 and 2001 had a boosting effect on many biotech disciplines and on the developments of polyhydroxyalkanoates (PHAs) in Switzerland in particular. The funding organization led by Prof. Oreste Ghisalba enabled a better understanding of the PHA biosynthesis and the development, as well as the implementation of novel bioprocesses (e.g. two-phase fermentations, multiple nutrient limited growth conditions, multi-stage chemostats, and product formation in different host organisms). However, production of PHA in Switzerland appeared to be impossible for cost reasons due to the strong competition from cheaper, petrol-based plastics. The recent reports on environmental issues with non-degradable plastics has triggered a general change in the perception of biodegradable plastics, giving them an added value and thus justifying a higher price. Ongoing research focuses on the sustainable production of PHAs using carbon waste streams, synthesis gas or even CO₂.


A novel big defensin identified in horseshoe crab hemocytes: isolation, amino acid sequence, and antibacterial activity.
Hemocytes of the horseshoe crab (limulus) contain a family of arthropodous peptide antibiotics, termed the tachyplesin family, and antibacterial protein, called anti-LPS factor, of which the former is located in the small (S) granules and the latter in the large (L) granules of the hemocytes. In our ongoing studies on granular components, we have identified here a novel defensin-like substance present in both L- and S-granules. This substance strongly inhibits the growth of Gram-negative and -positive bacteria, and fungi, such as Candida albicans. The isolated substance, tentatively termed "big defensin," consists of 79 amino acid residues, of which the COOH-terminal 37 residues have a sequence similar to those of mammalian neutrophil-derived defensins, especially rat defensin. Characterization of the disulfide motif in big defensin indicated that the disulfide array is identical to that of beta-defensins from bovine neutrophils. One clear structural difference is that the limulus hemocyte-derived big defensin has an extension of the NH2-terminal hydrophobic sequence with 35 amino acid residues followed by the COOH-terminal cationic defensin portion. This amphipathic nature of big defensin seems likely to be associated with its potent antibacterial activity. Furthermore, antibacterial activities of the NH2-terminal hydrophobic region and the COOH-terminal defensin portion separated by tryptic digestion are significantly different: the former displays a more potent activity against Gram-positive bacteria, whereas the latter is more potent against Gram-negative bacteria. Big defensin, therefore, may prove to represent a new class of defensin family possessing two functional domains with different antimicrobial activities.


Rapid detection of infectious pancreatic necrosis virus (IPNV) by the enzyme-linked immunosorbent assay (ELISA).
The enzyme-linked immunosorbent assay (ELISA) was used to demonstrate the presence of infectious pancreatic necrosis virus (IPNV) antigen in cell cultures and in fish. Virus antigen could be detected in infected cell cultures before visible cytopathic effect (c.p.e.) was evident and cell cultures showing complete viral c.p.e. produced intense colour reactions. Virus antigen was detected in infected fry during and immediately after an epizootic, but although IPNV-carrier fish could be detected by the ELISA technique, the sensitivity of detection was not as great as that of isolation of the infectious virus in cell culture. The major IPNV serotypes, Sp, Ab and Vr, crossreacted at only a low level and it was shown that the ELISA technique could be used to serotype IPNV strains rapidly. None of 10 other fish pathogenic viruses reacted with plates sensitized for IPNV detection. The time taken to perform the technique was reduced to 1 h 35 min at room temperature and this still allowed the results to be readily assessed visually as antigen-positive or antigen-negative.


Muramyl dipeptide mediated activation of human bronchial epithelial cells interacting with basophils: a novel mechanism of airway inflammation.
Respiratory tract bacterial infection can amplify and sustain airway inflammation. Intracytosolic nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is one member of the nucleotide binding and oligomerization domain (NOD)-like receptor (NLR) family, which senses the conserved structural peptidoglycan component muramyl dipeptide (MDP) in almost all bacteria. In the present study, activation of the NOD2 ligand MDP on primary human bronchial epithelial cells (HBE) co-cultured with human basophils was investigated. Cytokines, NOD2, adhesion molecules and intracellular signalling molecules were assayed by enzyme-linked immunosorbent assay or flow cytometry. The protein expression of NOD2 was confirmed in basophils/KU812 cells and HBE/human bronchial epithelial cell line (BEAS-2B) cells. MDP was found to up-regulate significantly the cell surface expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 on basophils and HBE in the co-culture system with or without basophil priming by interleukin (IL)-33 (all P < 0·05). MDP could further enhance the release of inflammatory cytokine IL-6 and chemokine CXCL8, and epithelium-derived anti-microbial peptide β-defensin 2 in the co-culture. HBE cells were the major source for the release of IL-6, CXCL8 and β-defensin2 upon stimulation by MDP in the co-culture system. The expression of ICAM-1 and VCAM-1 and release of IL-6 and CXCL8 were suppressed by various signalling molecule inhibitors, implying that the interaction between basophils and primary human bronchial epithelial cells could be regulated differentially by the mitogen-activated protein kinase pathways and nuclear transcription factors. The results therefore provide a new insight into the functional role of basophils in innate immunity, and the link between respiratory bacteria-mediated innate immunity and subsequent amplification of allergic inflammation in the airway.


Epinephrine potentiates adenosine-stimulating effect on glucagon secretion.
The aim of the present work is to investigate a possible interaction on glucagon secretion between adenosine, a compound released by tissues in energy-deficient states, and epinephrine, the hormone of stress largely implicated in such conditions. The study was performed using the isolated perfused rat pancreas in presence of a physiological glucose concentration (5 mM). Epinephrine administered at a low concentration (0.01 microM) was ineffective on glucagon secretion, and adenosine at 1.65 microM was previously shown to be moderately stimulating. This nucleoside alone induced a transient increase of glucagon secretion rate that peaked at 300% of basal value at 2 min; in presence of epinephrine (ineffective per se) the rise induced by the nucleoside alone was doubled. This potentiating effect was not observed with the neurotransmitter norepinephrine at the dose tested. Propranolol (1 microM) did not alter the potentiating effect of epinephrine but this effect was completely suppressed by the alpha-blocker, phenoxybenzamine (6 microM). In conclusion epinephrine potentiates an adenosine-stimulating effect on glucagon secretion; this effect seems more specific for the adrenal medulla hormone epinephrine, since norepinephrine at the same dose is ineffective; it is mediated via alpha-adrenergic receptors. It is attractive to speculate that epinephrine and adenosine act in potentiating synergism on glucagon secretion; this might be of physiological importance during stressful energy-deficient situations.


An assessment of the relationship between informal caring and quality of life in older community-dwelling adults - more positives than negatives?
The main objective of the study was to apply the recently developed Index of Capability (ICECAP-O) instrument to measure and value the quality of life of a representative sample of the older South Australian population (aged ≥ 65 years) according to carer status. A Health Omnibus survey including the ICECAP-O instrument, carer status (informal carer vs. non-carer) and several socio-demographic questions was administered in 2009 as a face-to-face interview to 789 individuals aged 65 years or older in their own homes. A total of 671 individuals (85%) characterised themselves as a non-carer and 115 individuals (15%) characterised themselves as an informal carer. In general, carers exhibited relatively high quality of life as measured by the ICECAP-O, with carers having comparable mean ICECAP-O scores to non-carers in the general population [carers: mean (SD) 0.848 (0.123), non-carers: mean (SD) 0.838 (0.147)]. The results of the multivariate regression model for the total sample indicated statistically significant variations in overall ICECAP-O scores according to age (with younger participants tending to have slightly higher scores on average), country of birth (with those participants who were born in Australia having higher scores on average than those who were born elsewhere) and household income (with participants with higher income levels having higher scores on average). The results of the multivariate regression model differentiated by carer status also indicated some important differences. Specifically, average ICECAP-O scores were noticeably lower for carers who are separated or divorced and for carers who lived alone and these differences were statistically significant. The study findings provide support for the existence of process utility in informal care-giving. The provision of informal care may be associated with a positive impact upon quality of life for many caregivers, which may mediate the negative aspects arising from the burden associated with informal care-giving.


The Assessment of Endovascular Therapies in Ischemic Stroke: Management, Problems and Future Approaches.
Ischemic stroke accounts for over 80% of all strokes and is one of the leading causes of mortality and permanent disability worldwide. Intravenous administration of recombinant tissue plasminogen activator (rt-PA) is an approved treatment strategy for acute ischemic stroke of large arteries within 4.5 h of onset, and mechanical thrombectomy can be used for large arteries occlusion up to 24 h after onset. Improving diagnostic work up for acute treatment, reducing onset-to-needle time and urgent radiological access angiographic CT images (angioCT) and Magnetic Resonance Imaging (MRI) are real problems for many healthcare systems, which limits the number of patients with good prognosis in real world compared to the results of randomized controlled trials. The applied endovascular procedures demonstrated high efficacy, but some cellular mechanisms, following reperfusion, are still unknown. Changes in the morphology and function of mitochondria associated with reperfusion and ischemia-reperfusion neuronal death are still understudied research fields. Moreover, future research is needed to elucidate the relationship between continuously refined imaging techniques and the variable structure or physical properties of the clot along with vascular permeability and the pleiotropism of ischemic reperfusion lesions in the penumbra, in order to define targeted preventive procedures promoting long-term health benefits.


Antibodies to watch in 2022.
In this 13th annual installment of the annual 'Antibodies to Watch' article series, we discuss key events in commercial antibody therapeutics development that occurred in 2021 and forecast events that might occur in 2022. Regulatory review of antibody therapeutics that target the SARS-CoV-2 coronavirus proceeded at an unprecedented pace in 2021, resulting in both emergency use authorizations and full approvals for sotrovimab, regdanvimab, REGEN-COV2, as well as others, in numerous countries. As of November 1, a total of 11 antibody therapeutics had been granted first approvals in either the United States or European Union in 2021 (evinacumab, dostarlimab loncastuximab tesirine, amivantamab, aducanumab, tralokinumab, anifrolumab, bimekizumab, tisotumab vedotin, regdanvimab, REGEN-COV2). The first global approvals of seven products, however, were granted elsewhere, including Japan (pabinafusp alfa), China (disitamab vedotin, penpulimab, zimberelimab), Australia (sotrovimab, REGEN-COV2), or the Republic of Korea (regdanvimab). Globally, at least 27 novel antibody therapeutics are undergoing review by regulatory agencies. First actions by the Food and Drug Administration on the biologics license applications for faricimab, sutimlimab, tebentafusp, relatlimab, sintilimab, ublituximab and tezepelumab are expected in the first quarter of 2022. Finally, our data show that, with antibodies for COVID-19 excluded, the late-stage commercial clinical pipeline of antibody therapeutics grew by over 30% in the past year. Of those in late-stage development, marketing applications for at least 22 may occur by the end of 2022.


[The calligrapher and the doctor].
Famous Turkish calligrapher Musa Azmi Hamid Aytaç (Am'idi) partially known life story and his family has been summarised by his relatives. The only three tougra like unpublished original calligrafics which has designed by Hamid to his relatives "l) Dr. Fethi Aksu, 2) Feridun Aksu, 3) Fikret Aksu" has been presented in this brief biography.


Clinical benefit of liver stiffness measurement at 3 months after Kasai hepatoportoenterostomy to predict the liver related events in biliary atresia.
The progression of hepatic fibrosis may result in decompensated hepatic failure with cirrhosis, liver related events (LRE) such as ascites, variceal bleeding, and death after successful and timely Kasai hepatoportoenterostomy (HPE) in biliary atresia. The aim of this study is to suggest clinical benefit of the liver stiffness measurement (LSM) using transient elastography at 3 months after the Kasai operation to predict LRE. Between January 2007 and December 2011, 69 eligible biliary atresia patients who underwent Kasai HPE and performed transient elastography before and 3 months after HPE were included. The occurrences of LRE were analyzed for all patients. All patients were divided into 2 groups (with and without LRE) for comparison. Multivariate analysis was used to detect the independent risk factors of LRE. The area under the receiver operation characteristics curve (AUROC) was used to establish the LSM optimal cutoff value of 3 months after Kasai operation in predicting LRE. LSM value, aminotransferase, albumin, bilirubin, and PT-INR significantly differed among the two groups. Multivariate analysis demonstrated LSM value as the most powerful independent factor of the development of LRE. The cut-off value of 19.9 kPa was calculated to be optimal for predicting LRE development with total sensitivity and specificity of 1.804. AUROC resulted in 0.943, with sensitivity of 85.3% and specificity of 95.2%. The LSM value of 3 months after Kasai HPE can be a useful predictor of LRE development.


Characterization of drug-resistance mutations in HIV type 1 isolates from drug-naive and ARV-treated patients in Bulgaria.
Little information is available about the prevalence of resistance mutations to reverse transcriptase (RT) and protease (PR) inhibitors of HIV-1, after the introduction of antiretroviral treatment in Bulgaria. To fill this gap, we analyzed 80 plasma samples from HIV-1-infected Bulgarian patients, 22 naive at antiretroviral treatment (ARV) and 58 ARV experienced. The subtypes B and A resulted in the two most prevalent (41 patients and 18 patients, respectively). The proportion of subtype B among naive and treated patients was similar in each group (57% vs. 47%, p = 0.62), while a major proportion of subtypes A was present in drug-naive patients rather than in treated patients [8/22 (36.4%) vs. 10/58 (17.2%), p = 0.08]. Two (9.1%) naive patients and 40 (70.1%) drug-experienced patients had viruses carrying at least one mutation conferring resistance to ARV drugs. Of 57 patients having experience with nucleoside reverse transcriptase inhibitors (NRTI), 32 (56.1%) had NRTI resistance mutations; 8/14 (57.2%) patients having experience with non-NRTI (NNRTI) had viruses carrying NNRTI resistance mutations; and 21/46 (45.7%) patients having experience with protease inhibitors (PI) had PI resistance mutations. The commonest resistance mutations resulted in the NRTI mutation M184V (42.1%) and the PI mutation L90M (24.1%). In conclusion, due to the detection of the substantial transmission of resistant variants to newly infected individuals, continuous surveillance is required, since greater access to highly active antiretroviral therapy (HAART) will be expected in Bulgaria. Furthermore, surveillance of PR and RT sequences is also convenient to monitor the introduction of nonsubtype B HIV-1 strains in Bulgaria.


Obstetric and perinatal outcomes of singleton pregnancies conceived via assisted reproductive technology complicated by gestational diabetes mellitus: a prospective cohort study.
Growing evidence indicates that the risk of obstetric and perinatal outcomes is higher in women with assisted reproductive technology (ART). However, there is little known about pregnancy related complications and co-morbidity in gestational diabetes mellitus (GDM) following singleton pregnancies achieved by ART in comparison with spontaneous conception (SC). Two hundred sixty singleton pregnant women conceived by ART and 314 pregnant women conceived by spontaneous conception (SC) were participated in this prospective cohort study. All participants were enrolled after GDM screening through one-step oral glucose tolerance test (OGTT) and then grouped into GDM and non-GDM groups. Women were followed for pregnancy outcomes including pregnancy-induced hypertension (PIH), preeclampsia, antepartum hemorrhage (APH), cesarean section (CS), preterm birth (PTB), intrauterine growth restriction (IUGR), being small or large for gestational age (SGA or LGA), macrosomia, low birth weight (LBW), respiratory distress, neonatal hypoglycemia, NICU admission and perinatal mortality from antenatal visits to delivery. Confounding factors were adjusted in logistic regression model in order to estimate adjusted odds ratios (aORs). Among 260 ART and 314 SC, 135 and 152 women were GDM women, respectively. Higher maternal age and pre-gravid BMI, shorter duration of gestation and lower gestational weight gain were observed in GDM groups (ART-GDM and SC-GDM) compared to those of the SC group. ART-GDM group had a higher risk (95% confidence interval) of obstetric complications including PIH [aOR:7.04 (2.24-22.15)], preeclampsia [aOR:7.78 (1.62-37.47)], APH [aOR:3.46 (1.28-9.33)], emergency CS [aOR:2.64 (1.43-4.88)], and perinatal outcomes such as PTB [aOR:3.89 (1.51-10.10)], LBW [aOR:3.11 (1.04-9.30)] and NICU admission [aOR:4.36 (1.82-10.45)], as well as neonatal hypoglycemia [aOR: 4.91 (1.50-16.07)], compared to SC group. SC-GDM group showed a higher risk of PIH [aOR: 4.12 (1.31-12.89)], emergency CS [aOR: 2.01 (1.09-3.73] and LGA [aOR: 5.20 (1.07-25.20)], compared to SC group. Additionally, ART group had a higher risk of PIH [aOR: 3.46(1.02-11.68), preeclampsia 5.29 (1.03-27.09), and NICU admission [aOR: 2.53 (1.05-6.09)] compared to SC. Insulin requirement (41.8% vs. 25.7%) was significantly higher in ART-GDM group compared to SC-GDM group. The findings of this study suggest that GDM occurring after ART conception increases the risk of adverse obstetric and perinatal outcomes.


BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study.
Influenza-related morbidity and mortality remain high. Seasonal vaccination is the backbone of influenza management but does not always result in protective antibody titers. Nonspecific effects of BCG vaccination related to enhanced function of myeloid antigen-presenting cells have been reported. We hypothesized that BCG vaccination could also enhance immune responses to influenza vaccination. Healthy volunteers received either live attenuated BCG vaccine (n = 20) or placebo (n = 20) in a randomized fashion, followed by intramuscular injection of trivalent influenza vaccine 14 days later. Hemagglutination-inhibiting (HI) antibodies and cellular immunity measured by ex vivo leukocyte responses were assessed. In BCG-vaccinated subjects, HI antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain were significantly enhanced, compared with the placebo group, and there was a trend toward more-rapid seroconversion. Additionally, apart from enhanced proinflammatory leukocyte responses following BCG vaccination, nonspecific effects of influenza vaccination were also observed, with modulation of cytokine responses against unrelated pathogens. BCG vaccination prior to influenza vaccination results in a more pronounced increase and accelerated induction of functional antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain. These results may have implications for the design of vaccination strategies and could lead to improvement of vaccination efficacy.


Identification Of Erythromyeloid Progenitors And Their Progeny In The Mouse Embryo By Flow Cytometry.
Macrophages are professional phagocytes from the innate arm of the immune system. In steady-state, sessile macrophages are found in adult tissues where they act as front line sentinels of infection and tissue damage. While other immune cells are continuously renewed from hematopoietic stem and progenitor cells (HSPC) located in the bone marrow, a lineage of macrophages, known as resident macrophages, have been shown to be self-maintained in tissues without input from bone marrow HSPCs. This lineage is exemplified by microglia in the brain, Kupffer cells in the liver and Langerhans cells in the epidermis among others. The intestinal and colon lamina propria are the only adult tissues devoid of HSPC-independent resident macrophages. Recent investigations have identified that resident macrophages originate from the extra-embryonic yolk sac hematopoiesis from progenitor(s) distinct from fetal hematopoietic stem cells (HSC). Among yolk sac definitive hematopoiesis, erythromyeloid progenitors (EMP) give rise both to erythroid and myeloid cells, in particular resident macrophages. EMP are only generated within the yolk sac between E8.5 and E10.5 days of development and they migrate to the fetal liver as early as circulation is connected, where they expand and differentiate until at least E16.5. Their progeny includes erythrocytes, macrophages, neutrophils and mast cells but only EMP-derived macrophages persist until adulthood in tissues. The transient nature of EMP emergence and the temporal overlap with HSC generation renders the analysis of these progenitors difficult. We have established a tamoxifen-inducible fate mapping protocol based on expression of the macrophage cytokine receptor Csf1r promoter to characterize EMP and EMP-derived cells in vivo by flow cytometry.


A mobile phone application for the assessment and management of youth mental health problems in primary care: health service outcomes from a randomised controlled trial of mobiletype.
GPs detect at best 50c of mental health problems in young people. Barriers to detecting mental health problems include lack of screening tools, limited appointment times and young people's reluctance to report mental health symptoms to GPs. The mobiletype program is a mobile phone mental health assessment and management application which monitors mood, stress and everyday activities then transmits this information to general practitioners (GPs) via a secure website in summary format for medical review. The current aims were to examine: (i) mobiletype as a clinical assistance tool, ii) doctor-patient rapport and, iii) pathways to care. We conducted a randomised controlled trial in primary care with patients aged 14 to 24 years recruited from rural and metropolitan general practices. GPs identified and referred eligible participants (those with mild or more mental health concerns) who were randomly assigned to either the intervention group (where mood, stress and daily activities were monitored) or the attention-comparison group (where only daily activities were monitored). Both groups self-monitored for 2 to 4 weeks and reviewed the monitoring data with their GP. GPs, participants and researchers were blind to group allocation at randomisation. GPs assessed the mobiletype program as a clinical assistant tool. Doctor-patient rapport was assessed using the General Practice Assessment Questionnaire Communication and Enablement subscales, and the Trust in Physician Scale (TPS). Pathways to care was measured using The Party Project's Exit Interview. Of the 163 participants assessed for eligibility, 118 were randomised and 114 participants were included in analyses (intervention n = 68, attention-comparison n = 46). T-tests showed that the intervention program increased understanding of patient mental health, assisted in decisions about medication/referral and helped in diagnosis when compared to the attention-comparison program. Mixed model analysis showed no differences in GP-patient rapport nor in pathways to care. We conducted the first RCT of a mobile phone application in the mental health assessment and management of youth mental health in primary care. This study suggests that mobiletype has much to offer GPs in the often difficult and time-consuming task of assessment and management of youth mental health problems in primary care. ClinicalTrials.gov NCT00794222.


A mutation in the 3-phosphoglycerate kinase gene allows anaerobic growth of Bacillus subtilis in the absence of ResE kinase.
The Bacillus subtilis ResD-ResE two-component signal transduction system is essential for aerobic and anaerobic respiration. A spontaneous suppressor mutant that expresses ResD-controlled genes and grows anaerobically in the absence of the ResE histidine kinase was isolated. In addition, aerobic expression of ResD-controlled genes in the suppressed strain was constitutive and occurred at a much higher level than that observed in the wild-type strain. The suppressing mutation, which mapped to pgk, the gene encoding 3-phosphoglycerate kinase, failed to suppress a resD mutation, suggesting that the suppressing mutation creates a pathway for phosphorylation of the response regulator, ResD, which is independent of the cognate sensor kinase, ResE. The pgk-1 mutant exhibited very low but measurable 3-phosphoglycerate kinase activity compared to the wild-type strain. The results suggest that accumulation of a glycolytic intermediate, probably 1, 3-diphosphoglycerate, is responsible for the observed effect of the pgk-1 mutation on anaerobiosis of resE mutant cells.


Nefopam Hydrochloride: A Fatal Overdose.
Nefopam is a non-opiate analgesic commonly used for the treatment of moderate to severe pain. A case of a 37-year-old male who was found dead in the morning is presented. An autopsy was performed and femoral venous blood, heart blood, urine, and vitreous humor were submitted for toxicological analysis. A general drug screen detected the presence of nefopam, caffeine, nicotine, citalopram, gabapentin, amitriptyline, diazepam and paracetamol in cardiac blood. Nefopam was quantitated by high-performance liquid chromatography with diode-array detection. Nefopam was found at the following concentrations: 13.6 mg/L in unpreserved femoral blood; 14.7 mg/L in preserved (fluoride-oxalate) femoral blood; 21.2 mg/L in unpreserved cardiac blood and 4.5 mg/L in preserved vitreous. Citalopram was present at a concentration of 0.7 mg/L (femoral blood) and 0.9 mg/L (cardiac blood). Ethanol analyzed by headspace gas chromatography (GC-FID) was detected in preserved (fluoride-oxalate) vitreous (14 mg/100 mL) and preserved (fluoride-oxalate) urine 50 mg/100 mL. Death was attributed to atherosclerotic coronary artery disease and therapeutic drug toxicity.


Role of PRKCM (PKCmu) in radiation-induced increase of JUN proto-oncogene mRNA levels in B-lineage lymphoid cells.
Exposure of cells to ionizing radiation results in both activation of protein kinase C (PRKC, also known as PKC) and induction of transcription of the JUN proto-oncogene. PRKC plays a pivotal role in radiation-induced JUN expression, since inhibition of PRKC abrogates the JUN signal. However, the specific PRKC isoforms involved in radiation-induced elevation of JUN mRNA levels have not been identified. Here we demonstrate that in DT40 B-lineage lymphoid cells, the mu isoform of PRKC (PRKCM) is critical for the response of JUN to ionizing radiation. The zinc chelator, 1, 10-phenanthroline, abrogated induction of JUN after exposure to ionizing radiation, indicating that this PRKCM-mediated response is also dependent on zinc.